Nephrology Dialysis Transplantation, Vol 13, Issue 7 1652-1661, Copyright © 1998 by Oxford University Press
D Goumenos, K Tsomi, C Iatrou, S Oldroyd, A Sungur, D Papaioannides, G Moustakas, P Ziroyannis, T Mountokalakis and A El Nahas
Background: The cellular and humoral factors involved
in the pathogenesis of glomerulosclerosis and renal fibrosis following a
crescentic glomerulonephritis have not been fully elucidated.
Myofibroblasts and transforming growth factor-{beta} (TGF-{beta})
have been implicated in the development of experimental and clinical renal
fibrosis. We have attempted to identify these mediators in crescentic
glomerulonephritis and determine their role in the progression of the
disease. Patients and methods. We have studied
retrospectively 21 patients with crescentic and necrotizing
glomerulonephritis (CNG) with emphasis on the renal expression (detected by
immunohistochemistry) of myofibroblasts (&agr;-smooth muscle
actin+ cells), TGF-{beta} and collagen (III and
IV) as well as their relationship with the clinical outcome of these
patients. In situ hybridization histochemistry was
applied to determine the site of synthesis of TGF-{beta}1 and collagen
III. All the patients were treated by immunosuppression and followed up for
a median period of 14 months. Results: Myofibroblasts
and TGF-{beta} were detected in the crescents as well as in the
periglomerular and tubulointerstitial areas in CNG biopsies. TGF-{beta}1
was also detected within renal tubular cells. The percentage of glomeruli
with fibrotic and fibrocellular crescents was positively correlated with
the severity of Bowman's capsule disruption (r-0.631, P<0.01) and
with the intensity of myofibroblast expression in the interstitium
(r-0.504, P<0.05). Strong interstitial immunostain for
myofibroblasts and TGF-{beta} was also noted in association with
interstitial fibrosis. In situ hybridization revealed
the site of synthesis of TGF-{beta}1 to be the renal tubular cells of
patients with CNG. By contrast, the site of synthesis of collagen III
appeared to be confined to interstitial cells surrounding vessels, tubules
and the glomeruli in a distribution identical to that of myofibroblasts.
There was a significant positive correlation between the number of
interstitial &agr;-SMA+ cells and both
interstitial TGF-{beta} (r=0.591, P<0.01) and interstitial
collagen IV (r=0.588, P<0.01). In addition, the number of
interstitial &agr;-SMA+ cells and the extent of
immunostain for collagen IV were positively correlated with the final serum
creatinine (r=0.517, P<0.05 and r=0.612, P<0.01 respectively)
and partially predicted functional outcome (R2=26.7%
and 37.5% respectively) as well as the response to treatment. An
association was observed between periglomerular myofibroblasts and the
generation of fibrotin and fibrocellular crescents.
Conclusion: These observations suggest a causal link
between myofibroblasts and fibrotic crescent formation. We also believe
that interstitial myofibroblasts are actively involved in the pathogenesis
of interstitial fibrosis in CNG. Key words:
Myofibroblasts; TGF-{beta} crescentic necrotizing glomerulonephritis
ORIGINAL ARTICLES
Myofibroblasts and the progression of crescentic glomerulonephritis
3rd University Department of Medicine, 'Sotiria' General Hospital, Department of Renal Pathology, 'Evangelismos' General Hospital, Department of Nephrology, General Hospital of Athens, Athens, Greece; Corresponding author at: Sheffield Kidney Institute, Northern General Hospital Trust, Herries Road, Sheffield S5 7AU, UK
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